Abstract: PO1549
Suppressed Autophagic Flux in the Heart in a Hypomorphic Pkd1 Mouse Model of ADPKD
Session Information
- Cystic Kidney Diseases: Emerging Concepts, Biomarkers, and Clinical Trials
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Atwood, Daniel, Univ Colorado, Aurora, Colorado, United States
- Brown, Carolyn Nicole, Univ Colorado, Aurora, Colorado, United States
- Hopp, Katharina, Univ Colorado, Aurora, Colorado, United States
- Edelstein, Charles L., Univ Colorado, Aurora, Colorado, United States
Background
Heart disease is largely unexplored in mouse models of ADPKD. The aim of the study was to determine mTOR signaling and autophagy in the heart in Pkd1RC/RC (RC) mice
Methods
Proteins were determined by immunoblot analysis. Mice were treated with autophagy inducers 2-deoxyglucose (2-DG) or Tat-Beclin1 peptide (Tat).
Results
There was increased heart weight/body weight ratio (HW/BW) in 180 d old RC mice. In 70 day old RC hearts, there was no increase in mTOR but a large increase in p-AMPKThr172, a known autophagy inducer. In 150 day old RC hearts, there was an increase in p-S6, p-AktThr308, p-GSK3β, p-AMPK, p-Beclin, an autophagy regulator and activating molecule in Beclin-1-regulated autophagy (AMBRA1). There was suppressed autophagic flux (lack of an increase in LC3-II, a marker of autophagosomes, with the lysosomal inhibitor bafilomycin-Baf), in 70 and 150 d old RC hearts compared to an increase in wild type (WT) hearts. In 120 d old RC hearts there was no increase in proliferation (PCNA) or apoptosis (TUNEL). Both 2-DG and Tat treatment increased heart weight and had no effect on kidney weight
Conclusion
There was a large increase in p-AMPK and suppressed autophagy in RC hearts. Unexpectedly, autophagy inducers increased heart weight
Age (days) | WT | RC | |
HW/BW (%) | 150 | 0.49 | 0.52 |
HW/BW (%) | 180 | 0.57 | 0.71*** |
Densitometry | |||
p-S6 | 120 | 0.7 | 1.3* |
p-Akt | 120 | 0.6 | 1.5* |
p-GSK3B | 120 | 1.1 | 1.4* |
p-AMPK | 70/120 | 0.5 | 1.5** |
p-Beclin | 120 | 0.3 | 0.7* |
AMBRA | 120 | 0.3 | 0.8** |
WT Veh | WT Baf | ||
LC3-II | 70 | 0.9 | 1.7* |
LC3-II | 120 | 0.6 | 1.3* |
RC Veh | RC Baf | ||
LC3-II | 70 | 0.2 | 0.3 |
LC3-II | 120 | 0.9 | 0.9 |
HW/BW (%) | RC | RC+Tx | |
2-DG | 150-350 | 0.54 | 0.59 |
Tat | 70-120 | 0.53 | 0.62* |
2K/BW (%) | |||
2-DG | 150-350 | 2.8 | 2.7 |
Tat | 70-120 | 2.4 | 2.3 |
*P<0.05, **P<0.01. ***P<0.001
Funding
- Veterans Affairs Support